Abstract LB030: Mechanisms of ERK action in MEK inhibitor-insensitive lung cancers
Authors: Ana Martin-Vega, Svetlana Eartnest, John D. Minna, Jane E. Johnson, Melanie H. Cobb
Journal: Cancer Research (2022)

Abstract Small cell lung cancer (SCLC) and other neuroendocrine (NE) lung tumors account for 25% of all lung cancers, they are the most aggressive type and have the poorest prognosis. SCLC does not present driver oncogenes involved in the regulation of kinase signaling, which makes these tumors hard to treat. The few available treatments yield responses early, but relapse occurs and they become resistant. Due to the poor efficacy of therapies, research in SCLC had been moved to the background, with basically no progress over the past decades. Mutations in the RAS-ERK pathway, elevating ERK activity and enhancing tumorigenesis, are common in other types of cancer, including NSCLC. Nevertheless, they are rare in SCLC. Indeed, previous studies demonstrated that ERK activation interferes with growth of SCLC. However, the mechanism by which ERK hinders tumor progression has not been defined yet. One of the most important players in SCLC and other NE tumors is the transcription factor ASCL1, essential for their survival. It has been reported that ASCL1 increases DUSP6 transcription with the consequent ERK activity suppression. Its downregulation affects cell cycle progression and survival. Conversely, inhibition of ERK activation by MEK inhibitors increases ASCL1 mRNA levels. Previous studies in our laboratory suggested that DUSP6 has a major role in a subset of SCLC and NSCLC-NE cell lines. Inhibition of DUSP6 enhances ERK signaling and significantly decreases survival of NE lung tumor cells. We have considered DUSP6 a good candidate to try to understand the mechanism by which ERK interferes with survival. However, hurdles in studying DUSP6 in SCLC include off-target effects of inhibitors and difficulty of gene-edited cell lines. To date, we have been able to generate a DUSP6 KO NSCLC-NE cell line which shows a clear drop in proliferation. Also, the overexpression of ERK or a constitutively active MEK1 mutant in a few SCLC, NE-NSCLC and MEK inhibitor-insensitive squamous lung cancer cell lines render a decrease in survival. DUSP6 is a cytoplasmic anchor for ERK and may reduce the ability of ERK to suppress ASCL1 transcription. For this reason, we are working on studying the effect on survival of ERK localization in the nucleus or the cytoplasm. With our ongoing experiments we are defining the conditions to examine transcriptional impact of ERK on SCLC. Discovering molecular events antagonized by the ERK pathway in SCLC will reveal novel targets controlling the inhibitory mechanisms. One of the SCLC major questions of translational relevance is what are the mechanisms upholding the development of chemoresistance, where the ERK pathway seems to be involved. Hence, the definition of the underlying mechanisms of tumorigenesis and therapy resistance will uncover new potential antitumor targets that currently escape our notice. A better understanding of the molecular biology of SCLC will let us find new therapeutic strategies to overcome the impasse in chemotherapy. Citation Format: Ana Martin-Vega, Svetlana Eartnest, John D. Minna, Jane E. Johnson, Melanie H. Cobb. Mechanisms of ERK action in MEK inhibitor-insensitive lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB030.